Forkhead box protein O1

Last updated
FOXO1
Protein FOXO1 PDB 3CO6.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FOXO1 , FKH1, FKHR, FOXO1A, forkhead box O1
External IDs OMIM: 136533 MGI: 1890077 HomoloGene: 1527 GeneCards: FOXO1
Orthologs
SpeciesHumanMouse
Entrez

2308

56458

Ensembl

ENSG00000150907

ENSMUSG00000044167

UniProt

Q12778

Q9R1E0

RefSeq (mRNA)

NM_002015

NM_019739

RefSeq (protein)

NP_002006

NP_062713

Location (UCSC) Chr 13: 40.56 – 40.67 Mb Chr 3: 52.18 – 52.26 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. [5] FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. [6] It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state. [7] [8]

Contents

Function

Adipogenesis

FOXO1-dependent inhibition of adipogenesis FOXO1 adipogenesis.jpg
FOXO1-dependent inhibition of adipogenesis

FOXO1 negatively regulates adipogenesis. [9] Presently, the exact mechanism by which this is accomplished is not entirely understood. In the currently accepted model, FOXO1 negatively regulates adipogenesis by binding to the promoter sites of PPARG and preventing its transcription. Rising levels of PPARG are required to initiate adipogenesis; by preventing its transcription, FOXO1 is preventing the onset of adipogenesis. During stimulation by insulin, FOXO1 is excluded from the nucleus and is subsequently unable to prevent transcription of PPARG and inhibit adipogenesis. [10] However, there is substantial evidence to suggest that there are other factors that mediate the interaction between FOXO1 and the PPARG promoter, and that inhibition of adipogenesis is not entirely dependent on FOXO1 preventing transcription of PPARG. [11] The failure to commit to adipogenesis is primarily due to active FOXO1 arresting the cell in G0/G1 through activation of yet unknown downstream targets, with a putative target being SOD2. [12]

FOXO1 belongs to the forkhead family of transcription factors that are characterized by a distinct fork head domain. The specific function of this gene has not yet been determined; however, it may play a role in myogenic growth and differentiation. [13] FOXO1 is essential for the maintenance of human ESC pluripotency. This function is probably mediated through direct control by FOXO1 of OCT4 and SOX2 gene expression through occupation and activation of their respective promoters. [14] In hepatic cells this transcription factor seems to increase the expression of PEPCK and glycogen-6-phosphatase (the same enzymes that are blocked via the metformin/AMPK/SHP pathway). Blocking this transcription factor offers an opportunity for novel therapies for diabetes mellitus. [15] In pancreatic alpha-cells FOXO1 is important in regulating prepro-glucagon expression. [16] In pancreatic beta cells FOXO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass. [17]

Gluconeogenesis and glycogenolysis

Depicts insulin-regulated nuclear exclusion of FOXO1 and its effect on transcription of glucose-6 phosphatase Foxo1 glucose stim.pdf
Depicts insulin-regulated nuclear exclusion of FOXO1 and its effect on transcription of glucose-6 phosphatase

When the level of blood glucose is high, the pancreas releases insulin into the bloodstream. Insulin then causes the activation of PI3K, which subsequently phosphorylates Akt. Akt then phosphorylates FOXO1, causing nuclear exclusion. [18] [19] This phosphorylated FOXO1 is then ubiquitinated and degraded by the proteosome. [20] The phosphorylation of FOXO1 is irreversible; this prolongs insulin's inhibitory effect on glucose metabolism and hepatic glucose production. Transcription of glucose 6-phosphatase subsequently decreases, which consequently decreases the rates of gluconeogenesis and glycogenolysis. [21] FOXO1 also activates transcription of phosphoenolpyruvate carboxykinase, which is required for gluconeogenesis. [22] The activity of FOXO1 is also regulated through CBP induced acetylation [23] on Lys-242, Lys-245, and Lys-262. These lysine residues are located within the DNA-binding domain; acetylation inhibits the ability of FOXO1 to interact with the glucose-6 phosphatase promoter by decreasing the stability of the FOXO1-DNA complex. Additionally, this acetylation increases the rate of phosphorylation on Ser-253 by Akt. Mutating Ser-253 to Ala-253 makes FOXO1 constitutively active. SIRT1 reverses this acetylation process; however, the exact mechanism by which SIRT1 deacetylates FOXO1 is still under investigation; presently, acetylation is thought to mitigate the transcriptional activity of FOXO1 and thereby provide an additional level of metabolic regulation that is independent of the insulin/PI3K pathway. [24]

Apoptosis

FOXO1 may play an important role in apoptosis because it is phosphorylated and inhibited by AKT. [25] When FOXO1 is over expressed in human LNCaP prostate cancer cells, it causes apoptosis. [25] Also, FOXO1 regulates TNF-related apoptosis-inducing ligand (TRAIL), which caused FOXO1-induced apoptosis in the human prostate cancer cell line LAPC4 when FOXO1 adenovirus-mediated overexpression was used. [25] FOXO1 upregulates Fas ligand (FasL) transcriptionally resulting in apoptotic cell death. [25] Additionally, FOXO1 trans-activate Bim protein, which a member of the Bcl-2 family that promotes apoptosis and plays a role in the intrinsic mitochondrial apoptotic pathway. [25] Further, it was revealed that DNA damage-induced cell death in p53-deficient and p53-proficient cells was reduced when human FOXO1 is silenced by siRNA. [25] In type 2 diabetes the beta cells of the pancreas, which normally produce insulin undergo apoptosis, which greatly reduces insulin production. Fatty acids in the beta cells activate FOXO1, resulting in apoptosis of the beta cells. [26]


Cell Cycle Regulation

FOXO1 activation plays a role in cell cycle progression regulation. [25] The transcription and half- life of cyclin-dependent kinase inhibitor p27KIP1 rises when FOXO1 is active. [25] A study detects that FOXO1 regulates the nuclear localization of p27KIP1 in porcine granulosa cells and impacts cell cycle progression. [25] Furthermore, FOXO1-mediated cell cycle arrest is linked with cyclin D1 and cyclin D2 suppression in mammals. [25] It was detected that human FOXO1 is linked with the cyclin D1 promoter using chromatin immunoprecipitation assays (ChIP assays). [25] H215R is a human FOXO1 mutant, which cannot bind to the canonical FRE to induce expression of p27KIP1, repress cyclin D1 and cyclin D2 promoter activity and encourages cell cycle arrest at cyclin G1 (CCNG1). [25] As a result of that, activation of FOXO1 prevents the cell-division cycle at cyclin G1 (CCNG1) out of one of two ways stimulating or suppressing gene transcription. [25]

Mechanism of action

In its un-phosphorylated state, FOXO1 is localized to the nucleus, where it binds to the insulin response sequence located in the promoter for glucose 6-phosphatase and increases its rate of transcription. FOXO1, through increasing transcription of glucose-6-phosphatase, indirectly increases the rate of hepatic glucose production. [22] However, when FOXO1 is phosphorylated by Akt on Thr-24, Ser-256, and Ser-319, it is excluded from the nucleus, where it is then ubiquitinated and degraded. The phosphorylation of FOXO1 by Akt subsequently decreases the hepatic glucose production through a decrease in transcription of glucose 6-phosphatase.

Regulation

There are three processes, namely acetylation, phosphorylation, and ubiquitination that are responsible for regulation of the activity of forkhead box O1 (FOXO1). [27]

Phosphorylation

Phosphorylation of the FOXO1 protein is a result of the activation of the PI3K /AKT pathway. [27] Serum and glucocorticoid-inducible kinase SGK can also phosphorylate and inactivate FOXO1 transcription factor. [25] FOXO1 translocate from the nucleus to cytoplasm and inactivate through phosphorylation at well-defined sites by AKT/SGK1 protein kinases. [27] FOXO1 transcription factor can phosphorylate directly by AKT/SGK1 on three sites T24, S256 and S319. [28] Additionally, FOXO1 loses its interactions with DNA when phosphorylated by AKT/SGK1 because S256, which is one of the three AKT/SGK sites, changes the DNA-binding domain charge from a positive charge to a negative charge. [27]

Insulin signaling substrates 1 and 2 of the insulin-signaling cascade also regulate FOXO1 through phosphorylation by AKT. [27] AKT, which is referred to as protein kinase B, phosphorylates FOXO1 and accumulates in the cytosol. [27]

Casein kinase 1, a growth factor-activated protein kinase, also phosphorylates and potentiates FOXO1 and translocates FOXO1 to the cytoplasm. [27]

Research

Because FOXO1 provides a link between transcription and metabolic control by insulin, it is also a potential target for genetic control of type 2 diabetes. In the insulin-resistant murine model, there is increased hepatic glucose production due to a loss in insulin sensitivity; the rates of hepatic gluconeogenesis and glycogenolysis are increased when compared to normal mice; this is presumably due to un-regulated FOXO1. When the same experiment was repeated with haploinsufficient FOXO1, insulin sensitivity was partially restored, and hepatic glucose production subsequently decreased. [29] Similarly, in mice fed with a high fat diet (HFD), there is increased insulin resistance in skeletal and liver cells. However, when haploinsufficient FOXO1 mice were treated with the same HFD, there was a notable decrease in insulin resistance in both skeletal and liver cells. This effect was significantly augmented by the simultaneous administration of rosiglitazone, which is a commonly prescribed anti-diabetic drug. [30] These results create an opportunity for a novel gene therapy based approach to alleviating insulin desensitization in type 2 diabetes.

In diabetes (both type 1 and type 2), gluconeogenesis in the kidney contributes more to blood glucose than it does in normal subjects. [31] Enhancing suppression of FOXO1 by insulin can reduce gluconeogenesis in both the liver and kidney. [31]

In HFD-fed mice, the combination of FOXO1 and Notch-1 haploinsufficiency was more effective at restoring insulin sensitivity than FOXO1 haploinsufficiency alone. [32]

Insulin-producing cells could be generated through the inhibition of FOXO1 in intestinal organoids generated from intestinal stem cells isolated from adult tissue. [33]

Clinical significance

Interactions

FOXO1 has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">Pyruvate kinase</span> Class of enzymes

Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">GSK-3</span> Class of enzymes

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen synthase (GS), GSK-3 has since been identified as a protein kinase for over 100 different proteins in a variety of different pathways. In mammals, including humans, GSK-3 exists in two isozymes encoded by two homologous genes GSK-3α (GSK3A) and GSK-3β (GSK3B). GSK-3 has been the subject of much research since it has been implicated in a number of diseases, including type 2 diabetes, Alzheimer's disease, inflammation, cancer, addiction and bipolar disorder.

<span class="mw-page-title-main">Restriction point</span> Animal cell cycle checkpoint

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<span class="mw-page-title-main">Protein kinase B</span> Set of three serine/threonine-specific protein kinases

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In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

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<span class="mw-page-title-main">RELA</span> Protein-coding gene in the species Homo sapiens

Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene.

<span class="mw-page-title-main">AKT2</span> Protein-coding gene in the species Homo sapiens

AKT2, also known as RAC-beta serine/threonine-protein kinase, is an enzyme that in humans is encoded by the AKT2 gene. It influences metabolite storage as part of the insulin signal transduction pathway.

<span class="mw-page-title-main">FOXO3</span> Protein-coding gene in the species Homo sapiens

Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.

<span class="mw-page-title-main">FOXO4</span> Protein

Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.

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<span class="mw-page-title-main">Daf-16</span> Ortholog

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<span class="mw-page-title-main">KLF15</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">FOXO6</span> Protein-coding gene in the species Homo sapiens

Forkhead box O6 is a protein that in humans is encoded by the FOXO6 gene.

Shaodong Guo is a Chinese-American nutrition scientist, academic, and diabetes researcher. He is a professor in nutrition and medicine at the Department of Nutrition of Texas A&M University. He has been a senior editor for Journal of Endocrinology and Journal of Molecular Endocrinology.

References

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